US6391853B1ExpiredUtility

Human tissue inhibitor of metalloproteinase-4

41
Assignee: HUMAN GENOME SCIENCES INCPriority: Dec 13, 1994Filed: Mar 4, 1999Granted: May 21, 2002
Est. expiryDec 13, 2014(expired)· nominal 20-yr term from priority
Inventors:John GreeneCraig Rosen
A61P 43/00A61K 48/00A61P 29/00A61P 3/02C07K 14/8146A61K 38/00C12N 2799/026
41
PatentIndex Score
2
Cited by
24
References
106
Claims

Abstract

A human tissue inhibitor of metalloproteinases-4 polypeptide and DNA (RNA) encoding such polypeptide and a procedure for producing such polypeptide by recombinant techniques. Also disclosed are methods for utilizing such polypeptide for the treatment of diseases, including arthritis and cancer. Antagonists against such polypeptides and their use as a therapeutic to resorb scar tissue are also disclosed. Diagnostic assays for detecting levels of human TIMP-4 protein and mutations in human TIMP-4 nucleic acid sequence are also disclosed.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
       1. A method for the treatment of a patient having need of TIMP-4 comprising: administering to the patient a therapeutically effective amount of a polypeptide selected from the group consisting of: 
       (a) a polypeptide having the deduced amino acid sequence of SEQ ID NO:2 and fragments thereof;  
       (b) a polypeptide comprising amino acid 1 to amino acid 195 of SEQ ID NO:2; and  
       (c) a polypeptide encoded by the cDNA of ATCC Deposit No. 75946 and fragments of said polypeptide;  
       wherein said polypeptide and said fragments inhibit metalloproteinase activity. 
     
     
       2. A method of inhibiting metalloproteinase activity which comprises, contacting a metalloproteinase with an amount of a polypeptide effective to inhibit metalloproteinase activity, wherein said polypeptide has an amino acid sequence selected from the group consisting of: 
       (a) at least 30 amino acids of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity;  
       (b) a fragment of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said fragment retains metalloproteinase inhibiting activity;  
       (c) the amino acid sequence of a polypeptide which possesses metalloproteinase inhibiting activity wherein said amino acid sequence is encoded by a polynucleotide which hybridizes to a DNA consisting of a sequence complementary to SEQ ID NO:1 when incubated in Church buffer with 100 ug/ml denatured herring sperm DNA as a blocking agent followed by washing sequentially with 2×SSC/0.1% SDS and 0.2×SSC/0.1% SDS at 65° C.;  
       (d) a first amino acid sequence at least 90% identical to a second amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2, wherein said first amino acid sequence retains metalloproteinase inhibiting activity;  
       (e) at least 30 amino acids of the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity; and  
       (f) a fragment of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said fragment retains metalloproteinase inhibiting activity.  
     
     
       3. The method of  claim 2 , wherein said polypeptide comprises amino acid sequence (a). 
     
     
       4. The method of  claim 3 , wherein said polypeptide comprises the amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2. 
     
     
       5. The method of  claim 3 , wherein said polypeptide comprises the amino acid sequence shown as residues 2 to 224 in SEQ ID NO:2. 
     
     
       6. The method of  claim 3 , wherein said polypeptide comprises the amino acid sequence shown as residues 1 to 224 in SEQ ID NO:2. 
     
     
       7. The method of  claim 2 , wherein said polypeptide comprises amino acid sequence (b). 
     
     
       8. The method of  claim 2 , wherein said polypeptide comprises amino acid sequence (c). 
     
     
       9. The method of  claim 2 , wherein said polypeptide comprises amino acid sequence (d). 
     
     
       10. The method of  claim 2 , wherein said polypeptide comprises amino acid sequence (e). 
     
     
       11. The method of  claim 10 , wherein said polypeptide comprises the amino acid sequence of the mature polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       12. The method of  claim 10 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, excepting the N-terminal methionine. 
     
     
       13. The method of  claim 10 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       14. The method of  claim 2 , wherein said polypeptide comprises amino acid sequence (f). 
     
     
       15. The method of  claim 2 , wherein said polypeptide comprises a heterologous polypeptide sequence. 
     
     
       16. The method of  claim 2 , wherein said polypeptide is in a pharmaceutically acceptable carrier. 
     
     
       17. A method of inhibiting the destruction of cellular basement membranes in a patient which comprises, administering to the patient, a therapeutically effective amount of a polypeptide having an amino acid sequence selected from the group consisting of: 
       (a) at least 30 amino acids of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity;  
       (b) a fragment of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said fragment retains metalloproteinase inhibiting activity;  
       (c) the amino acid sequence of a polypeptide which possesses metalloproteinase inhibiting activity wherein said amino acid sequence is encoded by a polynucleotide which hybridizes to a DNA consisting of a sequence complementary to SEQ ID NO:1 when incubated in Church buffer with 100 ug/ml denatured herring sperm DNA as a blocking agent followed by washing sequentially with 2×SSC/0.1% SDS and 0.2×SSC/0.1% SDS at 65° C.;  
       (d) a first amino acid sequence at least 90% identical to a second amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2, wherein said first amino acid sequence retains metalloproteinase inhibiting activity;  
       (e) at least 30 amino acids of the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity; and  
       (f) a fragment of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said fragment retains metalloproteinase inhibiting activity.  
     
     
       18. The method of  claim 17 , wherein said polypeptide comprises amino acid sequence (a). 
     
     
       19. The method of  claim 18 , wherein said polypeptide comprises the amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2. 
     
     
       20. The method of  claim 18 , wherein said polypeptide comprises the amino acid sequence shown as residues 2 to 224 in SEQ ID NO:2. 
     
     
       21. The method of  claim 18 , wherein said polypeptide comprises the amino acid sequence shown as residues 1 to 224 in SEQ ID NO:2. 
     
     
       22. The method of  claim 17 , wherein said polypeptide comprises amino acid sequence (b). 
     
     
       23. The method of  claim 17 , wherein said polypeptide comprises amino acid sequence (c). 
     
     
       24. The method of  claim 17 , wherein said polypeptide comprises amino acid sequence (d). 
     
     
       25. The method of  claim 17 , wherein said polypeptide comprises amino acid sequence (e). 
     
     
       26. The method of  claim 25 , wherein said polypeptide comprises the amino acid sequence of the mature polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       27. The method of  claim 25 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, excepting the N-terminal methionine. 
     
     
       28. The method of  claim 25 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       29. The method of  claim 17 , wherein said polypeptide comprises amino acid sequence (f). 
     
     
       30. The method of  claim 17 , wherein said polypeptide comprises a heterologous polypeptide sequence. 
     
     
       31. The method of  claim 17 , wherein said polypeptide is in a pharmaceutically acceptable carrier. 
     
     
       32. A method of treating restenosis which comprises, administering to a patient, a therapeutically effective amount of polypeptide having an amino acid sequence selected from the group consisting of: 
       (a) at least 30 amino acids of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity;  
       (b) a fragment of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said fragment retains metalloproteinase inhibiting activity;  
       (c) the amino acid sequence of polypeptide which possesses metalloproteinase inhibiting activity wherein said amino acid sequence is encoded by a polynucleotide which hybridizes to a DNA consisting of a sequence complementary to SEQ ID NO:1 when incubated in Church buffer with 100 ug/ml denatured herring sperm DNA as a blocking agent followed by washing sequentially with 2×SSC/0.1% SDS and 0.2×SSC/0.1% SDS at 65° C.;  
       (d) a first amino acid sequence at least 90% identical to a second amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2, wherein said first amino acid sequence retains metalloproteinase inhibiting activity;  
       (e) at least 30 amino acids of the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity; and  
       (f) a fragment of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said fragment retains metalloproteinase inhibiting activity.  
     
     
       33. The method of  claim 32 , wherein said polypeptide comprises amino acid sequence (a). 
     
     
       34. The method of  claim 33 , wherein said polypeptide comprises the amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2. 
     
     
       35. The method of  claim 33 , wherein said polypeptide comprises the amino acid sequence shown as residues 2 to 224 in SEQ ID NO:2. 
     
     
       36. The method of  claim 33 , wherein said polypeptide comprises the amino acid sequence shown as residues 1 to 224 in SEQ ID NO:2. 
     
     
       37. The method of  claim 32 , wherein said polypeptide comprises amino acid sequence (b). 
     
     
       38. The method of  claim 32 , wherein said polypeptide comprises amino acid sequence (c). 
     
     
       39. The method of  claim 32 , wherein said polypeptide comprises amino acid sequence (d). 
     
     
       40. The method of  claim 32 , wherein said polypeptide comprises amino acid sequence (e). 
     
     
       41. The method of  claim 40 , wherein said polypeptide comprises the amino acid sequence of the mature polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       42. The method of  claim 40 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, excepting the N-terminal methionine. 
     
     
       43. The method of  claim 40 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       44. The method of  claim 32 , wherein said polypeptide comprises amino acid sequence (f). 
     
     
       45. The method of  claim 32 , wherein said polypeptide comprises a heterologous polypeptide sequence. 
     
     
       46. The method of  claim 32 , wherein said polypeptide is in a pharmaceutically acceptable carrier. 
     
     
       47. A method of treating cancer which comprises, administering to a patient, a therapeutically effective amount of a polypeptide having an amino acid sequence selected from the group consisting of: 
       (a) at least 30 amino acids of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity;  
       (b) a fragment of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said fragment retains metalloproteinase inhibiting activity;  
       (c) the amino acid sequence of a polypeptide which possesses metalloproteinase inhibiting activity wherein said amino acid sequence is encoded by a polynucleotide which hybridizes to a DNA consisting of a sequence complementary to SEQ ID NO:1 when incubated in Church buffer with 100 ug/ml denatured herring sperm DNA as a blocking agent followed by washing sequentially with 2×SSC/0.1% SDS and 0.2×SSC/0.1% SDS at 65° C.;  
       (d) a first amino acid sequence at least 90% identical to a second amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2, wherein said first amino acid sequence retains metalloproteinase inhibiting activity;  
       (e) at least 30 amino acids of the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity; and  
       (f) a fragment of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said fragment retains metalloproteinase inhibiting activity.  
     
     
       48. The method of  claim 47 , wherein said polypeptide comprises amino acid sequence (a). 
     
     
       49. The method of  claim 48 , wherein said polypeptide comprises the amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2. 
     
     
       50. The method of  claim 48 , wherein said polypeptide comprises the amino acid sequence shown as residues 2 to 224 in SEQ ID NO:2. 
     
     
       51. The method of  claim 48 , wherein said polypeptide comprises the amino acid sequence shown as residues 1 to 224 in SEQ ID NO:2. 
     
     
       52. The method of  claim 47 , wherein said polypeptide comprises amino acid sequence (b). 
     
     
       53. The method of  claim 47 , wherein said polypeptide comprises amino acid sequence (c). 
     
     
       54. The method of  claim 47 , wherein said polypeptide comprises amino acid sequence (d). 
     
     
       55. The method of  claim 47 , wherein said polypeptide comprises amino acid sequence (e). 
     
     
       56. The method of  claim 55 , wherein said polypeptide comprises the amino acid sequence of the mature polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       57. The method of  claim 55 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, excepting the N-terminal methionine. 
     
     
       58. The method of  claim 55 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       59. The method of  claim 47 , wherein said polypeptide comprises amino acid sequence (f). 
     
     
       60. The method of  claim 47 , wherein said polypeptide comprises a heterologous polypeptide sequence. 
     
     
       61. The method of  claim 47 , wherein said polypeptide is in a pharmaceutically acceptable carrier. 
     
     
       62. A method of inhibiting tumor invasion which comprises, administering to a patient, a therapeutically effective amount of a polypeptide having an amino acid sequence selected from the group consisting of: 
       (a) at least 30 amino acids of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity;  
       (b) a fragment of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said fragment retains metalloproteinase inhibiting activity;  
       (c) the amino acid sequence of a polypeptide which possesses metalloproteinase inhibiting activity wherein said amino acid sequence is encoded by a polynucleotide which hybridizes to a DNA consisting of a sequence complementary to SEQ ID NO:1 when incubated in Church buffer with 100 ug/ml denatured herring sperm DNA as a blocking agent followed by washing sequentially with 2×SSC/0.1% SDS and 0.2×SSC/0.1% SDS at 65° C.;  
       (d) a first amino acid sequence at least 90% identical to a second amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2, wherein said first amino acid sequence retains metalloproteinase inhibiting activity;  
       (e) at least 30 amino acids of the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity; and  
       (f) a fragment of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said fragment retains metalloproteinase inhibiting activity.  
     
     
       63. The method of  claim 62 , wherein said polypeptide comprises amino acid sequence (a). 
     
     
       64. The method of  claim 63 , wherein said polypeptide comprises the amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2. 
     
     
       65. The method of  claim 63 , wherein said polypeptide comprises the amino acid sequence shown as residues 2 to 224 in SEQ ID NO:2. 
     
     
       66. The method of  claim 63 , wherein said polypeptide comprises the amino acid sequence shown as residues 1 to 224 in SEQ ID NO:2. 
     
     
       67. The method of  claim 62 , wherein said polypeptide comprises amino acid sequence (b). 
     
     
       68. The method of  claim 62 , wherein said polypeptide comprises amino acid sequence (c). 
     
     
       69. The method of  claim 62 , wherein said polypeptide comprises amino acid sequence (d). 
     
     
       70. The method of  claim 62 , wherein said polypeptide comprises amino acid sequence (e). 
     
     
       71. The method of  claim 70 , wherein said polypeptide comprises the amino acid sequence of the mature polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       72. The method of  claim 70 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, excepting the N-terminal methionine. 
     
     
       73. The method of  claim 70 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       74. The method of  claim 62 , wherein said polypeptide comprises amino acid sequence (f). 
     
     
       75. The method of  claim 62 , wherein said polypeptide comprises a heterologous polypeptide sequence. 
     
     
       76. The method of  claim 62 , wherein said polypeptide is in a pharmaceutically acceptable carrier. 
     
     
       77. A method of inhibiting angiogenesis which comprises, administering to a patient, a therapeutically effective amount of a polypeptide having an amino acid sequence selected from the group consisting of: 
       (a) at least 30 amino acids of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity;  
       (b) a fragment of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said fragment retains metalloproteinase inhibiting activity;  
       (c) the amino acid sequence of a polypeptide which possesses metalloproteinase inhibiting activity wherein said amino acid sequence is encoded by a polynucleotide which hybridizes to a DNA consisting of a sequence complementary to SEQ ID NO:1 when incubated in Church buffer with 100 ug/ml denatured herring sperm DNA as a blocking agent followed by washing sequentially with 2×SSC/0.1% SDS and 0.2×SSC/0.1% SDS at 65° C.;  
       (d) a first amino acid sequence at least 90% identical to a second amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2, wherein said first amino acid sequence retains metalloproteinase inhibiting activity;  
       (e) at least 30 amino acids of the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity; and  
       (f) a fragment of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said fragment retains metalloproteinase inhibiting activity.  
     
     
       78. The method of  claim 77 , wherein said polypeptide comprises amino acid sequence (a). 
     
     
       79. The method of  claim 78 , wherein said polypeptide comprises the amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2. 
     
     
       80. The method of  claim 78 , wherein said polypeptide comprises the amino acid sequence shown as residues 2 to 224 in SEQ ID NO:2. 
     
     
       81. The method of  claim 78 , wherein said polypeptide comprises the amino acid sequence shown as residues 1 to 224 in SEQ ID NO:2. 
     
     
       82. The method of  claim 77 , wherein said polypeptide comprises amino acid sequence (b). 
     
     
       83. The method of  claim 77 , wherein said polypeptide comprises amino acid sequence (c). 
     
     
       84. The method of  claim 77 , wherein said polypeptide comprises amino acid sequence (d). 
     
     
       85. The method of  claim 77 , wherein said polypeptide comprises amino acid sequence (e). 
     
     
       86. The method of  claim 85 , wherein said polypeptide comprises the amino acid sequence of the mature polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       87. The method of  claim 85 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, excepting the N-terminal methionine. 
     
     
       88. The method of  claim 85 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       89. The method of  claim 77 , wherein said polypeptide comprises amino acid sequence (f). 
     
     
       90. The method of  claim 77 , wherein said polypeptide comprises a heterologous polypeptide sequence. 
     
     
       91. The method of  claim 77 , wherein said polypeptide is in a pharmaceutically acceptable carrier. 
     
     
       92. A method of inhibiting metastasis which comprises, administering to a patient, a therapeutically effective amount of a polypeptide having an amino acid sequence selected from the group consisting of: 
       (a) at least 30 amino acids of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity;  
       (b) a fragment of the amino acid sequence shown as residues 1 to 224 of SEQ ID NO:2, wherein said fragment retains metalloproteinase inhibiting activity;  
       (c) the amino acid sequence of a polypeptide which possesses metalloproteinase inhibiting activity wherein said amino acid sequence is encoded by a polynucleotide which hybridizes to a DNA consisting of a sequence complementary to SEQ ID NO:1 when incubated in Church buffer with 100 ug/ml denatured herring sperm DNA as a blocking agent followed by washing sequentially with 2×SSC/0.1% SDS and 0.2×SSC/0.1% SDS at 65° C.;  
       (d) a first amino acid sequence at least 90% identical to a second amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2, wherein said first amino acid sequence retains metalloproteinase inhibiting activity;  
       (e) at least 30 amino acids of the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said at least 30 amino acids retain metalloproteinase inhibiting activity; and  
       (f) a fragment of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, wherein said fragment retains metalloproteinase inhibiting activity.  
     
     
       93. The method of  claim 92 , wherein said polypeptide comprises amino acid sequence (a). 
     
     
       94. The method of  claim 93 , wherein said polypeptide comprises the amino acid sequence shown as residues 30 to 224 in SEQ ID NO:2. 
     
     
       95. The method of  claim 93 , wherein said polypeptide comprises the amino acid sequence shown as residues 2 to 224 in SEQ ID NO:2. 
     
     
       96. The method of  claim 93 , wherein said polypeptide comprises the amino acid sequence shown as residues 1 to 224 in SEQ ID NO:2. 
     
     
       97. The method of  claim 92 , wherein said polypeptide comprises amino acid sequence (b). 
     
     
       98. The method of  claim 92 , wherein said polypeptide comprises amino acid sequence (c). 
     
     
       99. The method of  claim 92 , wherein said polypeptide comprises amino acid sequence (d). 
     
     
       100. The method of  claim 92 , wherein said polypeptide comprises amino acid sequence (e). 
     
     
       101. The method of  claim 100 , wherein said polypeptide comprises the amino acid sequence of the mature polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       102. The method of  claim 100 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946, excepting the N-terminal methionine. 
     
     
       103. The method of  claim 100 , wherein said polypeptide comprises the amino acid sequence of the full-length polypeptide encoded by the human cDNA contained in ATCC Deposit No. 75946. 
     
     
       104. The method of  claim 92 , wherein said polypeptide comprises amino acid sequence (f). 
     
     
       105. The method of  claim 92 , wherein said polypeptide comprises a heterologous polypeptide sequence. 
     
     
       106. The method of  claim 92 , wherein said polypeptide is in a pharmaceutically acceptable carrier.

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